Asparaginase is an

enzyme Enzymes () are proteins that act as biological catalysts by accelerating chemical reactions. The molecules upon which enzymes may act are called substrates, and the enzyme converts the substrates into different molecules known as products. A ...

that is used as a medication and in

food manufacturing Food processing is the transformation of agricultural products into food, or of one form of food into other forms. Food processing includes many forms of processing foods, from grinding grain to make raw flour to home cooking to complex ind ...

. As a medication, L-asparaginase is used to treat

acute lymphoblastic leukemia Acute lymphoblastic leukemia (ALL) is a cancer of the lymphoid line of blood cells characterized by the development of large numbers of immature lymphocytes. Symptoms may include feeling tired, pale skin color, fever, easy bleeding or bruisin ...

(ALL) and

lymphoblastic lymphoma Acute lymphoblastic leukemia (ALL) is a cancer of the lymphoid line of blood cells characterized by the development of large numbers of immature lymphocytes. Symptoms may include feeling tired, pale skin color, fever, easy bleeding or bruisin ...

(LBL). It is given by

injection into a vein Intravenous therapy (abbreviated as IV therapy) is a medical technique that administers fluids, medications and nutrients directly into a person's vein. The intravenous route of administration is commonly used for rehydration or to provide nutrie ...

muscle Skeletal muscles (commonly referred to as muscles) are organs of the vertebrate muscular system and typically are attached by tendons to bones of a skeleton. The muscle cells of skeletal muscles are much longer than in the other types of muscl ...

, or under the skin. A

pegylated PEGylation (or pegylation) is the process of both covalent and non-covalent attachment or amalgamation of polyethylene glycol (PEG, in pharmacy called macrogol) polymer chains to molecules and macrostructures, such as a drug, therapeutic protein ...

version is also available. In food manufacturing it is used to decrease

acrylamide Acrylamide (or acrylic amide) is an organic compound with the chemical formula CH2=CHC(O)NH2. It is a white odorless solid, soluble in water and several organic solvents. From the chemistry perspective, acrylamide is a vinyl-substituted primary ...

. Common side effects when used by injection include allergic reactions,

pancreatitis Pancreatitis is a condition characterized by inflammation of the pancreas. The pancreas is a large organ behind the stomach that produces digestive enzymes and a number of hormones. There are two main types: acute pancreatitis, and chronic pancr ...

, blood clotting problems, high blood sugar, kidney problems, and liver dysfunction. Use in

pregnancy Pregnancy is the time during which one or more offspring develops ( gestates) inside a woman's uterus (womb). A multiple pregnancy involves more than one offspring, such as with twins. Pregnancy usually occurs by sexual intercourse, but ca ...

may harm the baby. As a food it is generally recognized as safe. Asparaginase works by breaking down the

amino acid Amino acids are organic compounds that contain both amino and carboxylic acid functional groups. Although hundreds of amino acids exist in nature, by far the most important are the alpha-amino acids, which comprise proteins. Only 22 alpha am ...

known as

asparagine Asparagine (symbol Asn or N) is an α-amino acid that is used in the biosynthesis of proteins. It contains an α-amino group (which is in the protonated −NH form under biological conditions), an α-carboxylic acid group (which is in the depro ...

without which the cancer cells cannot make

protein Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residues. Proteins perform a vast array of functions within organisms, including catalysing metabolic reactions, DNA replication, respo ...

. The most common nonhematological adverse reactions of asparaginase erwinia chrysanthemi (recombinant) include abnormal liver test, nausea, musculoskeletal pain, infection, fatigue, headache, febrile neutropenia, pyrexia, hemorrhage (bleeding), stomatitis, abdominal pain, decreased appetite, drug hypersensitivity, hyperglycemia, diarrhea, pancreatitis, and hypokalemia. Asparaginase was approved for medical use in the United States in 1978. It is on the World Health Organization's List of Essential Medicines. It is often made from ''

Escherichia coli ''Escherichia coli'' (),Wells, J. C. (2000) Longman Pronunciation Dictionary. Harlow ngland Pearson Education Ltd. also known as ''E. coli'' (), is a Gram-negative, facultative anaerobic, rod-shaped, coliform bacterium of the genus ''Escher ...

'' (''E. coli'') or ''

Erwinia chrysanthemi ''Dickeya dadantii'' is a gram-negative bacillus that belongs to the family Pectobacteriaceae. It was formerly known as ''Erwinia chrysanthemi'' but was reassigned as ''Dickeya dadantii'' in 2005. Members of this family are facultative anaerobes ...

''.

Uses

Asparaginases can be used for different industrial and pharmaceutical purposes.

Medical

E. coli ''Escherichia coli'' (),Wells, J. C. (2000) Longman Pronunciation Dictionary. Harlow ngland Pearson Education Ltd. also known as ''E. coli'' (), is a Gram-negative, facultative anaerobic, rod-shaped, coliform bacterium of the genus ''Escher ...

'' strains are the main source of medical asparaginase. Branded formulations (with different chemical and pharmacological properties) available in 1998 include Asparaginase Medac, Ciderolase, and Oncaspar. (Crasnitin has been discontinued.) Spectrila is a recombinant ''E. coli'' asparaginase. Asparaginase produced by ''

Dickeya dadantii ''Dickeya dadantii'' is a gram-negative bacillus that belongs to the family Pectobacteriaceae. It was formerly known as ''Erwinia chrysanthemi'' but was reassigned as ''Dickeya dadantii'' in 2005. Members of this family are facultative anaerobe ...

'' (formerly called ''Erwinia chrysanthemi'') instead is known as crisantaspase (

BAN Ban, or BAN, may refer to: Law * Ban (law), a decree that prohibits something, sometimes a form of censorship, being denied from entering or using the place/item ** Imperial ban (''Reichsacht''), a form of outlawry in the medieval Holy Roman ...

), and is available in the United Kingdom under the brand name Erwinase. One of the ''E. coli'' asparaginases marketed under the brand name Elspar for the treatment of

(ALL) is also used in some

mast cell tumor A mastocytoma or mast cell tumor is a type of round-cell tumor consisting of mast cells. It is found in humans and many animal species; it also can refer to an accumulation or nodule of mast cells that resembles a tumor. Mast cells originate f ...

protocols. On July 24, 2006, the U.S. Food and Drug Administration granted approval to pegaspargase for the first-line treatment of patients with acute lymphoblastic leukemia (ALL) as a component of a multiagent chemotherapy regimen. Pegaspargase was previously approved in February 1994 for the treatment of patients with ALL who were hypersensitive to native forms of L-asparaginase. On December 20, 2018, the Food and Drug Administration (FDA) approved calaspargase pegol-mknl, an asparagine specific enzyme, as a component of a multi-agent chemotherapeutic regimen for acute lymphoblastic leukemia (ALL) in pediatric and young adult patients age 1 month to 21 years. This new product provides for a longer interval between doses compared to other available pegaspargase products. Calaspargase pegol-mknl has received FDA orphan drug designation. On 30 June 2021, the U.S.

Food and Drug Administration The United States Food and Drug Administration (FDA or US FDA) is a List of United States federal agencies, federal agency of the United States Department of Health and Human Services, Department of Health and Human Services. The FDA is respon ...

(FDA) approved asparaginase erwinia chrysanthemi (recombinant)-rywn) as a component of a multi-agent chemotherapeutic regimen for the treatment of acute lymphoblastic leukemia (ALL) and lymphoblastic lymphoma (LBL) in people aged one month or older who have developed hypersensitivity to ''E. coli''-derived asparaginase. The FDA granted the application for asparaginase erwinia chrysanthemi (recombinant)-rywn fast track and

orphan drug An orphan drug is a pharmaceutical agent developed to treat medical conditions which, because they are so rare, would not be profitable to produce without government assistance. The conditions are referred to as orphan diseases. The assignment of ...

designations.

Food manufacturing

The most common use of asparaginases is as a processing aid in the manufacture of food. Asparaginases are used as a food processing aid to reduce the formation of

, a suspected

carcinogen A carcinogen is any substance, radionuclide, or radiation that promotes carcinogenesis (the formation of cancer). This may be due to the ability to damage the genome or to the disruption of cellular metabolic processes. Several radioactive substan ...

, in starchy food products such as snacks, biscuits and fried potato.

Side effects

The main side effect is an

allergic Allergies, also known as allergic diseases, refer a number of conditions caused by the hypersensitivity of the immune system to typically harmless substances in the environment. These diseases include hay fever, food allergies, atopic derma ...

or hypersensitivity reaction;

anaphylaxis Anaphylaxis is a serious, potentially fatal allergic reaction and medical emergency that is rapid in onset and requires immediate medical attention regardless of use of emergency medication on site. It typically causes more than one of the follow ...

is a possibility. Additionally, it can also be associated with a

coagulopathy Coagulopathy (also called a bleeding disorder) is a condition in which the blood's ability to coagulate (form clots) is impaired. This condition can cause a tendency toward prolonged or excessive bleeding (bleeding diathesis), which may occur spo ...

as it decreases protein synthesis, including synthesis of coagulation factors (e.g. progressive isolated decrease of fibrinogen) and anticoagulant factor (generally antithrombin III; sometimes protein C & S as well), leading to bleeding or thrombotic events such as stroke. Bone marrow suppression is common but only mild to moderate, rarely reaches clinical significance and therapeutic consequences are rarely required. Other common side effects include

. These side effects mainly attributes to the dual activity of L.Asparaginase as it can also hydrolysis L.Glutamine to Glutamic acid and ammonia.

Mechanism of action

As a food processing aid

Acrylamide is often formed in the cooking of starchy foods. During heating the

, naturally present in starchy foods, undergoes a process called the

Maillard reaction The Maillard reaction ( ; ) is a chemical reaction between amino acids and reducing sugars that gives browned food its distinctive flavor. Seared steaks, fried dumplings, cookies and other kinds of biscuits, breads, toasted marshmallows, and man ...

, which is responsible for giving baked or fried foods their brown color, crust, and toasted flavor. Suspected carcinogens such as acrylamide and some heterocyclic amines are also generated in the Maillard reaction. By adding asparaginase before baking or frying the food, asparagine is converted into another common amino acid,

aspartic acid Aspartic acid (symbol Asp or D; the ionic form is known as aspartate), is an α-amino acid that is used in the biosynthesis of proteins. Like all other amino acids, it contains an amino group and a carboxylic acid. Its α-amino group is in the pro ...

, and

ammonium The ammonium cation is a positively-charged polyatomic ion with the chemical formula or . It is formed by the protonation of ammonia (). Ammonium is also a general name for positively charged or protonated substituted amines and quaternary a ...

. As a result, asparagine cannot take part in the Maillard reaction, and therefore the formation of acrylamide is significantly reduced. Complete acrylamide removal is probably not possible due to other, minor asparagine-independent formation pathways. As a food processing aid, asparaginases can effectively reduce the level of acrylamide in a range of starchy foods without changing the taste and appearance of the end product.

As a drug

The rationale behind asparaginase is that it takes advantage of the fact that acute lymphoblastic leukemia cells and some other suspected tumor cells are unable to synthesize the

non-essential amino acid An essential amino acid, or indispensable amino acid, is an amino acid that cannot be synthesized from scratch by the organism fast enough to supply its demand, and must therefore come from the diet. Of the 21 amino acids common to all life form ...

asparagine, whereas normal cells are able to make their own asparagine; thus leukemic cells require high amount of asparagine. These leukemic cells depend on circulating asparagine. Asparaginase, however, catalyzes the conversion of L-asparagine to aspartic acid and ammonia. This deprives the leukemic cell of circulating asparagine, which leads to cell death.

Enzyme regulation

Type I L-asparaginase protein may use the

morpheein Morpheeins are proteins that can form two or more different homo-oligomers (morpheein forms), but must come apart and change shape to convert between forms. The alternate shape may reassemble to a different oligomer. The shape of the subunit ...

model of

allosteric regulation In biochemistry, allosteric regulation (or allosteric control) is the regulation of an enzyme by binding an effector molecule at a site other than the enzyme's active site. The site to which the effector binds is termed the ''allosteric site ...

Cost

Normal asparaginase costs less than its

version,

pegaspargase Pegaspargase, sold under the brand name Oncaspar, is a medication used in the treatment of acute lymphoblastic leukemia (ALL). Often it is used together with anthracycline, vincristine, and corticosteroids (for example prednisone and dexametha ...

. However, because it doesn't stay as long in the body, the injections need to be more frequent, with the result that total cost of treatment may be lower for the pegylated version.

History

The discovery and development of asparaginase as an anti-cancer drug began in 1953, when scientists first observed that lymphomas in

rat Rats are various medium-sized, long-tailed rodents. Species of rats are found throughout the order Rodentia, but stereotypical rats are found in the genus ''Rattus''. Other rat genera include ''Neotoma'' ( pack rats), ''Bandicota'' (bandicoot ...

and

mice A mouse ( : mice) is a small rodent. Characteristically, mice are known to have a pointed snout, small rounded ears, a body-length scaly tail, and a high breeding rate. The best known mouse species is the common house mouse (''Mus musculus' ...

regressed after treatment with guinea pig

serum Serum may refer to: *Serum (blood), plasma from which the clotting proteins have been removed **Antiserum, blood serum with specific antibodies for passive immunity * Serous fluid, any clear bodily fluid * Truth serum, a drug that is likely to mak ...

. Later it was found out that it is not the serum itself which provoke the tumour regression, but rather the enzyme asparaginase. After researchers comparing different kinds of asparaginases, the one derived from ''

'' and ''

'' turned out to have the best anti-cancer ability. ''E. coli'' has thereby become the main source of asparaginase due to the factor that it is also easy to produce in large amount. The pharmacokinetics of asparaginase erwinia chrysanthemi (recombinant) (Rylaze) were evaluated in 225 recipients in study JZP458-201 (NCT04145531), an open-label multicenter trial in which asparaginase erwinia chrysanthemi (recombinant) was administered at various dosages and routes, and the results were used to develop a model to predict serum asparaginase activity at various timepoints.

Society and culture

Names

Crisantaspase is the

British Approved Name A British Approved Name (BAN) is the official, non-proprietary, or generic name given to a pharmaceutical substance, as defined in the British Pharmacopoeia (BP). The BAN is also the official name used in some countries around the world, because ...

(BAN) for asparaginase obtained from ''

''. Colaspase is the BAN of asparaginase obtained from ''

''. The United States Adopted Name of crisantaspase is asparaginase ''Erwinia chrysanthemi''. Elspar, Kidrolase, Leunase and Spectrila are brand names for colaspase, while Erwinase and Erwinaze are brand names for crisantaspase. The

version of colaspase is called

. Oncaspar is the brand name of pegaspargase.

References

External links

* * * * {{Authority control EC 3.5.1 Antineoplastic drugs Orphan drugs World Health Organization essential medicines Wikipedia medicine articles ready to translate